Chimeric Mouse Developed to Test Human Liver Disease

Mouse liver containing 95 percent human hepatocytes.

A team led by Salk Institute researchers
has developed a mouse model with 95 percent of
its liver containing cells of human origin, making it
an ideal system to test novel therapies for debilitating
human diseases, including cancer.

The team, led by senior author Inder Verma,
a professor in the Laboratory of Genetics, had
previously generated a mouse with a partially
"humanized" liver, but wanted to improve their
method to achieve almost complete transformation.
They use a special mouse that has liver problems of
its own, but whose problems can be kept in check
with a drug called NBTC. Taking away NBTC allows
human hepatocytes to take hold and populate the
mouse liver with human cells.

The new model is susceptible to human liver
infections and responds to human drug treatments.
To test this, the researchers exposed the mice to
Hepatitis B and Hepatitis C and found that, unlike
normal mice, that are resistant to these viruses,
the chimeric animals developed the disease.

More importantly, using pegylated interferon
alpha 2a – the standard treatment for Hepatitis
C – the researchers showed that the "humanized"
liver inside the mouse responds just like a normal
human liver. The team tested additional experimental
drugs and found that they too behaved as
they did in humans.

"This shows that our chimeric mouse model
is medically relevant and can be used to validate
novel drugs in a pre-clinical setting," says first
author Karl-Dimiter Bissig, an internist and postdoctoral
researcher in the Laboratory of Genetics.
"This is great news as it provides us with a tool with
which we can examine many human hepatotropic
pathogens, including malaria. In the future, it also
has potential applications for regenerative medicine;
allowing confirmation of the true hepatocyte
nature of cells prior to human transplantation."

The study was published in the online edition of
the Journal of Clinical Investigation in February.